CN107921129A - Combination and application thereof - Google Patents

Combination and application thereof Download PDF

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CN107921129A
CN107921129A CN201680048061.2A CN201680048061A CN107921129A CN 107921129 A CN107921129 A CN 107921129A CN 201680048061 A CN201680048061 A CN 201680048061A CN 107921129 A CN107921129 A CN 107921129A
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CN107921129B (en
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J·恩德尔
M·温德尔里奇
R·博克斯哈默
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Morphosys AG
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
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    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
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    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/16—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation

Abstract

The present disclosure describes the drug regimen of 3 kinase inhibitor of anti-CD 19 antibodies and phosphoinositide for treating non-Hodgkin lymphoma, chronic lymphocytic leukemia and/or acute lymphoblastic leukemia.

Description

Combination and application thereof
Technical field
This disclosure relates to for treating non-Hodgkin lymphoma, chronic lymphocytic leukemia and/or acute into lymph The drug regimen of anti-the CD19 antibody and phosphoinositide 3-kinase inhibitor of cell leukemia.
Background technology
B cell is the lymphocyte to play a significant role in humoral immune response.They result from most of lactations and move In the marrow of thing, the 5-15% of circulation lymph (circulating lymphoid pool) is accounted for.The major function of B cell is The antibody for various antigens is prepared, and is the necessary component of adaptive immune system.
Due to their key effects in immune system is adjusted, the imbalance of B cell is with various diseases such as lymthoma and in vain Blood disease is related.These diseases include non-Hodgkin lymphoma (" NHL "), chronic lymphocytic leukemia (" CLL ") and acute Lymphoblastic leukemia (" ALL ").
NHL is derived from the heterogeneous malignant tumour of lymphocyte.At the U.S. (U.S.), incidence is estimated in 65,000/ years, Death toll be about 20,000 (American Cancer Society (American Cancer Society), 2006；With SEER Cancer Statistics Review).The disease may occur in institute's has age, start to break out in the adult usually more than 40 years old, send out Sick rate is with age.NHL is characterized in the clonal expansion for the lymphocyte accumulated in lymph node, blood, marrow and spleen, to the greatest extent Any major organs can be related to by managing it.The categorizing system that virologist and clinician use at present is the World Health Organization (WHO) staging method, NHL is organized into precursor and ripe B- cells or T- cell neoplasms by it.PDQ is at present by NHL It is inertia (indolent) or aggressive to be divided into for entering clinical test.Inertia NHL groups mainly include folliculus hypotype, small Lymphocytic lymphoma, MALT (mucosa-associated lymphoid tissue) and marginal zone；Inertia includes about 50% B- newly diagnosed Cell NHL patient.Aggressive NHL is primary diffusivity large B cell (DLBL, DLBCL or DLCL) (institute including histodiagnosis Have in the patient newly diagnosed 40% there is diffusivity maxicell), the patient of Burkitt's and jacket cell.The clinical process of NHL is Height change.The main determining factor of clinical process is histological subtypes.Most of inert type NHL are deemed to be and cannot cure Disease.Patient initially has response to chemotherapy or antibody therapy, most of to recur.Research so far not yet shows morning Phase intervenes the improvement to survival rate.In asymptomatic patient, " observe and wait " is acceptable, until patient shows disease Shape or progression of disease seem accelerating.With the propulsion of time, disease can be converted into more aggressive tectotype (histology).Median overall survival is 8-10, and the patient of inert type usually receives 3 times or more during the treatment of its disease Repeatedly treatment.Chemotherapy progress is had been combined in history to the initial treatment of Symptomatic inert type NHL patient.It is the most frequently used Medicine include：Endoxan, vincristine and prednisone (CVP)；Or endoxan, adriamycin, vincristine and prednisone (CHOP).About 70% to 80% patient will be initial to its chemotherapy have reaction, remission time will continue the amount of 2-3 Level.Final Most patients can recur.The discovery of anti-CD 20 antibodies Rituximab (rituximab) and Clinical practice are Provide significantly improving for response and survival rate.The nursing standard of Most patients is Rituximab+CHOP (R- at present ) or Rituximab+CVP (R-CVP) CHOP.Interferon is approved to be combined the initial treatment for NHL with alkylating drug, but The application in the U.S. is limited.Rituximab therapy shows it is effective in several NHL, is approved at present as inertia (follicular lymphoma) and invasion NHL (diffusivity large B cell lymphoid tumor) first-line treatment of the two.But anti-CD 20 Dan Ke Grand antibody (mAb) has obvious limitation, including primary drug resistance (50% response in recurrence inertia patient), acquired resistance (50% responsiveness during re-treatment), rare complete response (2% complete response rate in recurrence colony) and continuous recurrent pattern.Most Afterwards, many B cells do not express CD20, therefore many B- cell disorders are irremediable using anti-CD 20 antibodies therapy.
In addition to NHL, there is the leukaemia as caused by B cell dysregulation of several types.CLL is that a kind of B lymphs are thin Adult leukemia caused by born of the same parents' abnormal accumulation.In CLL, malignant lymphocytic may look like it is normal and ripe, but it Cannot effectively cope with infection.CLL is most common leukemic forms in adult.The possibility that male develops CLL is women Twice.But key risk factor is the age.More than 75% new case is diagnosed to be in the patient at more than 50 years old age. It is annual to be diagnosed to be more than 10,000 cases, death toll for almost 5,000 it is annual (American Cancer Society, 2006；And SEER Cancer Statistics Review).CLL is incurable disease, but is in most cases made slow progress.Many suffers from The people of CLL is normal, energetically lives many years.Since its morbidity is slow, early stage CLL is usually not treated, as it is believed that early stage CLL, which intervenes, will not improve life span or quality of life.Instead, the state of an illness is monitored with the time.Initial CLL is controlled Treat and depend on exact diagnosis and the development of disease and change.There are tens of kinds of medicines to be treated for CLL.Combination chemotherapy scheme is for example FCR (fludarabine (fludarabine), endoxan and Rituximab) and BR (Idelalisib and Rituximab) exist It is effective in CLL newly diagnose and recurrence.Allogenic bone marrow (stem cell) transplanting is seldom used as mono- lines of CLL due to its risk Treatment uses.
Another type of leukaemia is ALL, also referred to as acute lymphatic leukemia.ALL is characterized in marrow Pernicious, jejune leucocyte (also referred to as lymphoblast) excessively produces and continuous propagation." acute " refers to the lymph of circulation Undifferentiated, the jejune state of cell (" blastocyte " (blasts)), and disease develop rapidly, if not treatment is expected Service life is several weeks to the several months.ALL is most commonly in children, and onset peak is age 4-5 Sui.The children at age 12-16 Sui are more easy to extremely In the disease.At present, at least 80% children ALL is considered to be recoverable.Less than 4,000 cases are diagnosed to be every year, it is dead Number for almost 1,500 it is annual (American Cancer Society, 2006；With SEER Cancer Statistics Review).
19 molecules of people CD are the exact cell surface receptors of the structure expressed on human B cell surface, these B cell bags Include but be not limited to, the B cell (i.e. immature B cell) of pre B cell --- early development, by terminal differentiation become thick liquid cell Mature B cell and malignant B cell.CD 19 is by-B acute lymphoblastic leukemias (ALL), non-Hodgkin's before most of It is lymthoma, B cell chronic lymphocytic leukemia (CLL), pre-lymphocytic leukemia, hairy cell leukemia, common Acute lymphatic leukemia and some Null types acute lymphoblastic leukemias expression (Nadler et al., J.Immunol.,131:244-250(1983)；Loken et al., Blood, 70:1316-1324(1987)；Uckun et al., Blood,71:13-29(1988)；Anderson et al., 1984.Blood, 63:1424-1433(1984)；Scheuermann, Leuk.Lymphoma,18:385-397(1995)).Expression of the CD 19 on thick liquid cell further demonstrates that it can be in differentiation B cell tumour such as Huppert's disease, plasmacytoma, expression in Waldenstrom's tumours (Grossbard et al., Br.J.Haematol,102:509-15(1998)；Treon et al., Semin.Oncol, 30:248-52(2003)).
Therefore, CD19 antigens are non-Hodgkin lymphoma (including various hypotypes as described herein), chronic lymphocytic Immunotherapy target in the treatment of leukaemia and/or acute lymphoblastic leukemia.
Have shown that some CD19 therapies.CD3- ζ and 4-BB are included using expression to three patients with late period CLL The T cell of the anti-CD19 Chimeric antigen receptors (CAR) of costimulation domain.Kalos et al., T cells with Chimeric Antigen Receptors Have Potent Antitumor Effects and Can Establish Memory in Patients with Advanced Leukemia,Science Translational Medicine,vol.3,no.95 (on August 10th, 2011), it is integrally incorporated by quoting.By quoting Sadelain being integrally incorporated et al., The promise and potential pitfalls of chimeric antigen receptors,Current Opinion in Immunology, Elsevier, vol.21, no.2,2April 2009, also illustrates anti-CD19 Chimeric antigen receptors (CAR).
CD19 antibody is discussed in WO2007076950 (US2007154473) in non-specific B-cells lymthoma Purposes, this two documents are integrally incorporated by quoting.
In " the CD19Antigen in Leukemia and Lymphoma Diagnosis of Scheuermann et al. Described in and Immunotherapy, Leukemia and Lymphoma, Vol.18,385-397 (1995) " CLL, CD19 antibody is used in NHL and ALL, it is integrally incorporated by quoting.
In WO2005012493 (US7109304), WO2010053716 (US12/266,999) (Immunomedics)； WO2007002223(US8097703)(Medarex)；WO2008022152 (12/377,251) and WO2008150494 (Xencor)、WO2008031056(US11/852,106)(Medimmune)；WO 2007076950(US11/648,505) (Merck Patent GmbH)；WO 2009/052431(US12/253,895)(Seattle Genetics)；And WO2010095031 (12/710,442) (Glenmark Pharmaceuticals), WO2012010562 and WO2012010561 (International Drug Development), WO2011147834 (Roche Glycart) and WO2012/156455 (Sanofi) the specific antibody of other CD19 is described in, all of which is integrally incorporated by quoting.
WO2010151341(US13/377,514)(The Feinstein Institute)；US5686072 (University of Texas) and WO2002022212 (PCT/US01/29026) (IDEC Pharmaceuticals), WO2013/024097 (14/126,928) (MorphoSys AG) and WO2013/024095 (14/127,217) (MorphoSys AG the specific antibody of CD19 and the combination of other reagents are described in), its is all integrally incorporated by quoting.In April, 2014 The 5-9 days entitled Drug synergies observed in the AACR that San Diego, CA is held meetings in 2014 for antibody and toxin components of SAR3419ADC contribute to overall Conjugate efficacy and can be combination drug or tumor cell line dependent's Summary 4765 discloses the anti-CD19 antibody drugs conjugates of the SAR3419 containing the PI3K inhibitor in some cell lines (ADC)。
Some phosphoinositide 3-kinase inhibitors are commercially available.Idelalisib, also referred to as GS-1101 or CAL- 101, sold by Gilead, there is a trade name Zydelig in the U.S..In U.S. Patent No. 6,800,620；8,865,730；8, 980,901；RE44599；With describe Idelalisib in RE44638, all of which is integrally incorporated by quoting.
Obviously, although getting along with recently in the discovery and development of anticancer, it is related to many of the tumour of expression CD19 The cancer of form still has undesirable prognosis.Therefore, it is necessary to the method for improved this kind of cancer for the treatment of.
The content of the invention
The prior art is not both independent do not show that the combination of exemplary antibodies and Idelalisib are being treated in combination yet Synergistic effect in non-Hodgkin lymphoma, chronic lymphocytic leukemia and/or acute lymphoblastic leukemia.
On the one hand, this disclosure relates to the synergistic combination of CD19 specific antibodies and phosphoinositide 3-kinase inhibitor.So Combination can be used for treatment B cell malignant tumour, as non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia and/or Acute lymphoblastic leukemia (ALL).
How the combination that external model is considered indicating some compounds or compound works in the mankind.To a variety of Cell line is tested, for example, MEC-1 cells (DSMZ#ACC497) --- a kind of chronic B cell leukemia cell line.This MEC-1 cells in kind of external model show how combination will rise in the treatment of human chronic's lymphocytic leukemia (CLL) Effect.
In addition, when compound combines in vitro, people, which are expected combination, only has superposition.It is surprising that hair A person of good sense has found, compared with the single antibody and Idelalisib, specific antibodies and Idelalisib of the specificity for CD19 The horizontal specific cell of mediation collaboration is killed in vitro for combination.
Specifically, the inventors discovered that, compared with single antibody and Idelalisib, MOR00208 and The combination of Idelalisib horizontal specific cell of external mediation collaboration in MEC-1 cells is killed.
In addition, inventor has also been unexpectedly found that, compared with single antibody and Idelalisib, CD19 is specific The combination of specific antibodies and Idelalisib have some superior functional characteristics.
Make in short, the combination of exemplary anti-CD19 antibody and Idelalisib play collaboration in the model related with CLL With.Due to CLL be with the relevant illness of B cell, and CD19 altimeters in B cell reach, and exemplary combination will have identical Mechanism of action, and should also play synergistic effect in the treatment of other B cell associated conditions (such as NHL and ALL).
Therefore, the combination of exemplary CD19 specific antibodies and Idelalisib is in people's non-Hodgkin lymphoma, chronic Should be effective in the treatment of lymphocytic leukemia and/or acute lymphoblastic leukemia.Clinical test confirms Expection effect of exemplary CD19 specific antibodies and Idelalisib.
Since Idelalisib is similar with the mechanism of action of other phosphoinositide 3-kinase inhibitors, because they pass through suppression It is made as one or more phosphoinositide 3-kinases of a part for PI3K/AKT/mTOR paths and works, the PI3K/ AKT/mTOR paths are that important signal transduction is led to for such as growing control, metabolism and translation initiation to many cell functions Road, it is believed that controlled when with the combination of exemplary anti-CD19 antibody and the phosphoinositide 3-kinase inhibitor in addition to Idelalisib When treating the people with non-Hodgkin lymphoma, chronic lymphocytic leukemia and/or acute lymphoblastic leukemia It should be appreciated that synergistic effect.
Due to exemplary anti-CD19 antibody and other anti-CD19 antibody bindings CD19, resisted so working as with any anti-CD19 Body is with phosphoinositide 3-kinase inhibitor (such as Idelalisib) treatment with non-Hodgkin lymphoma, chronic lymphocytic During the people of leukaemia and/or acute lymphoblastic leukemia, it should also see synergistic effect.
An aspect of this disclosure includes CD19 specific antibodies and the synergistic combination of Idelalisib, and wherein CD19 is special Heterogenetic antibody includes：Sequence SYVMH (SEQ ID NO:1) HCDR1 areas, sequence NPYNDG (SEQ ID NO:2) HCDR2 Area, sequence GTYYYGTRVFDY (SEQ ID NO:3) HCDR3 areas, sequence RSSKSLQNVNGNTYLY (SEQ ID NO:4) LCDR1 areas, sequence RMSNLNS (SEQ ID NO:5) LCDR2 areas and sequence MQHLEYPIT (SEQ ID NO:6) LCDR3 Area.At preferable aspect, the combination be used to treating non-Hodgkin lymphoma, chronic lymphocytic leukemia and/or it is acute into Lymphocytic leukemia.
Brief description of the drawings
Fig. 1 shows the amino acid sequence of the variable domains of MOR00208.
Fig. 2 shows the amino acid sequence in the Fc areas of MOR00208.
Fig. 3-6 shows the combination of MOR00208 and Idelalisib from four independent experiments in MEC-1 cells ADCC dose response curves.
Fig. 7-10 shows the combination of the MOR00208 and Idelalisib of the various dose from four independent experiments CI curves.
Embodiment
" concertedness ", " synergistic effect " or " collaboration " refers to the expection Overlay more than combination.Herein, combine " concertedness ", " synergistic effect " or " collaboration " the effect method that passes through Chou et al., Clarke et al. and/or Webb et al. Determine.Referring to：Ting-Chao Chou, the theoretical foundation of synergistic effect and antagonism, experimental design in drug regimen research With calculating simulation (Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies),Pharmacol Rev 58: 621-681 (2006), are incorporated by as reference herein.Turning also now to：In Clarke et al., breast cancer and other models The problem of in experimental cell toxic agents In vivo study in experimental design and end point analysis (Issues in experimental design and endpoint analysis in the study of experimental cytotoxic agents in vivo in breast cancer and other models),Breast Cancer Research and Treatment 46:255-278 (1997), is incorporated by as reference herein.Turning also now to：Webb, J.L. (1963) enzyme and metabolism press down Preparation (Enzyme and Metabolic Inhibitors), Academic Press, New York, herein by its full text simultaneously Enter as reference.
Term " antibody " refers to monoclonal antibody, including any isotype, for example, IgG, IgM, IgA, IgD and IgE.IgG Antibody is made of two identical heavy chains and two identical light chains, it is connected by disulfide bond.Each heavy chain and light chain contain There are constant region and variable region.Three sections for being referred to as " complementary determining region " (" CDR ") or " hypervariable region " are contained in each variable region, its It is mainly responsible for and is combined with epitope.They are referred to as CDR1, CDR2 and CDR3, from N- ends number consecutively.Variable region in CDR Exterior more highly conserved part is referred to as " skeleton area "." antibody fragment " refers to Fv, scFv, dsFv, Fab, Fab'F (ab') 2 fragments or other fragments, it contains at least one variable heavy chain or variable light each containing CDR and skeleton area.
" phosphoinositide 3-kinase inhibitor " is a kind of medicine, it is used as the one of PI3K/AKT/mTOR paths by suppressing Partial one or more phosphoinositide 3-kinases and work, the PI3K/AKT/mTOR paths to many cell functions such as It is important signal transduction pathway for growth control, metabolism and translation initiation.
PI3K has many different classifications and isotype.I classes PI3K has the catalytic subunit for being known as p110, has four species Type (isotype)-p110 α, p110 β, p110 γ and p110 δ.The inhibitor studied at present suppresses the one or more of I classes PI3K Isotype.
Phosphoinositide 3-kinase inhibitor includes at least Idelalisib, Duvelisib and Copanlisib.
Idelalisib is by Gilead Sciences, and (trade name Zydelig, is also designated as GS-1101 for Inc. sale Or CAL-101).Idelalisib is noted as being used for following treatment at present：Because of other comorbidities therefore rituximab alone Be considered as appropriate therapies patient in, with Rituximab combined treatment recurrence chronic lymphocytic leukemia (CLL)； The follicular B cell non-Hodgkin lymphoma of recurrence is treated in the patient at least receiving systemic treatment first twice (FL)；The small lymphocyte lymthoma (SLL) of recurrence is treated in the patient at least receiving whole body therapeutic first twice.Should Material works as phosphoinositide 3-kinase inhibitor；More specifically, it blocks the δ of this enzyme of phosphoinositide 3-kinase sub- Type P110 δ.The chemical formula of Idelalisib is：
Duvelisib (IPI-145, INK1197) is a kind of new selective PI3K δ/γ (δ and γ) inhibitor. The chemical formula of Duvelisib is：
It is that a kind of selectivity I classes phosphoinositide 3-kinase suppresses by the Bayer Copanlisib (BAY 80-6946) developed Agent.The chemical formula of Copanlisib is：
" VH " refers to the variable region of the heavy chain immunoglobulin of antibody or antibody fragment." VL " refers to antibody or antibody fragment Light chain immunoglobulin variable region.
Term " CD19 " refers to the referred to as albumen of CD19, it is with following synonym：B4, B- lymphocyte antigen CD19, B- lymphocyte surface antigens B4, CVID3, differentiation antigen CD19, MGC12802 and t cell surface antigen Leu-12.
People CD19 has following amino acid sequence：
MPPPRLLFFLLFLTPMEVRPEEPLVVKVEEGDNAVLQCLKGTSDGPTQQLTWSRESPLKPFLKLSLGLPGLGIHMRP LAIWLFIFNVSQQMGGFYLCQPGPPSEKAWQPGWTVNVEGSGELFRWNVSDLGGLGCGLKNRSSFGPSSPSGKLMSP KLYVWAKDRPFIWFGFPPCLPPRDSLNQSLSQDLTMAPGSILWLSCGVPPDSVSRGPLSWTHVHPKGPKSLLSLELK DDRPARDMWVMETGLLLPRATAQDAGKYYCHRGNLTMSFHLEITARPVLWHWLLRTGGWKVSAVTLAYLIFCLCSLV GILHLQRALVLRRKRKRMTDPTRRFFKVTPPPGSGPQNQYGNVLSLPTPTSGLGRAQRWAAGLGGTAPSYGNPSSDV QADGALGSRSPPGVGPEEEEGEGYEEPDSEEDSEFYENDSNLGQDQLSQDGSGYENPEDEPLGPEDEDSFSNAESYE NEDEELTQPVARTMDFLSPHGSAWDPSREATSLGSQSYEDMRGILYAAPQLRSIRGQPGPNHEEDADSYENMDNPDG PDPAWGGGGRMGTWSTR.(SEQ ID NO：7)
" MOR00208 " is a kind of anti-CD19 antibody.The amino acid sequence of variable domains is provided in Fig. 1.Carried in Fig. 2 The heavy chain of MOR00208 and the amino acid sequence in light chain Fc areas are supplied." MOR00208 ", " XmAb 5574 " and " MOR208 " by with Make synonym to describe the antibody shown in Fig. 1 and 2.Described in U.S. Patent Application Serial Number 12/377,251 MOR00208 antibody, wherein Whole light chains are SEQ ID NO：106, entire heavy chain is SEQ ID NO：87, it is whole by quoting Body is incorporated to.
It has studied in ALL, NHL, CLL and the human clinical trial of small lymphocyte lymthoma (SLL) MOR00208。
U.S. Patent No. 7,109,304 (Immunomedics) (it is integrally incorporated by quoting)；U. S. application sequence Row number 11/917,750 (Medarex) (it is integrally incorporated by quoting)；Application U.S. Serial No 11/852,106 (Medimmune) (it is integrally incorporated by quoting)；Application U.S. Serial No 11/648,505 (Merck Patent GmbH) (it is integrally incorporated by quoting)；(it is by quoting entirety simultaneously for U.S. Patent No. 7,968,687 (Seattle Genetics) Enter)；With Application U.S. Serial No 12/710,442 (Glenmark Pharmaceuticals) (it is integrally incorporated by quoting) In describe other antibody specific to CD19.
" Fc areas " refers to the constant region of antibody, it can be the subclass of IgG1,2,3,4 or other in the mankind.Human Fc area Sequence can be in IMGT, Human IGH C-REGIONs, http：//www.imgt.org/IMGTrepertoire/ Proteins/protein/human/IGH/IGHC/Hu_IGHCallgenes.html (retrieval on May 16th, 2011) is obtained.
" RefmAb33 " is the antibody for having following amino acid sequence：
Heavy chain includes Fc areas：
QVTLRESGPALVKPTQTLTLTCTFSGFSLSTAGMSVGWIRQPPGKALEWLADIWWDDKKHYNPSLKDRLTISKDTSK NQVVLKVTNMDPADTATYYCARDMIFNFYFDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFP EPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP CPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSV LTVVHQDWLNGKEYKCKVSNKALPAPEEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWE SNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO： 8)
Light chain includes Fc areas：
DIQMTQSPSTLSASVGDRVTITCSASSRVGYMHWYQQKPGKAPKLLIYDTSKLASGVPSRFSGSGSGTEFTLTISSL QPDDFATYYCFQGSGYPFTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQ SGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO：9)
RefmAb33 is specific for RSV, because itself and MOR00208 enjoy identical Fc areas, as isotype pair According to.
" combination " refers to be more than one, for example, compound such as antibody and Idelalisib.
The disclosure further relates to include combination, medicine and the pharmaceutical composition of the combination.Two of synergistic combination of the present invention Component, such as CD19 specific antibodies and Idelalisib, can be physically or on the time together, at the same time, respectively or then Administration.
Idelalisib takes orally 150mg twice daily at present.The current intravenous administrations of MOR00208, at present weekly administration one It is secondary or be administered once every two weeks.In one embodiment, applied before CD19 specific antibodies (such as MOR00208) are applied Use Idelalisib.In one embodiment, applied after CD19 specific antibodies (such as MOR00208) are applied Idelalisib。
Preferably, two kinds of applying for medicine allow two kinds of medicines active in patients at the same time.If for example, MOR00208 Weekly administration and Idelalisib daily administrations, then even if two kinds of medicines are not always being applied on the same day, ideally, The active material of two kinds of medicines is also present in patient's body at the same time.
" at the same time " or " applying together " refers to both components in two kinds of components (medicine) while active in patients When apply." synergistic effect " implies that two kinds of medicines are active in patients at the same time." at the same time " or " applying together " need not refer to The exact same time is applying medicine on the same day always.
Both components can be configured to different pharmaceutical compositions.
Pharmaceutical composition includes activating agent, such as a kind of antibody for human treatment.Pharmaceutical composition can include can The carrier or excipient of receiving.
" administration " or " administration " includes but not limited to, and is delivered by injectable forms, it includes for example intravenous, muscle In interior, intracutaneous, local, percutaneous, peritonaeum, in eye socket；Pass through implantation or subcutaneous route or mucosal route, such as nasal spray or suction Enter by the use of aerosol or taken orally as the solution that can be taken in or as capsule or tablet.
Compound or " therapeutically effective amount " of combination are to refer to realize measurable improvement, alleviate or partly suppress given The amount of the clinical manifestation of disease or illness.Effective amount will be serious depending on disease or injury for particular treatment purposes Property and the weight and general status of subject.It is to be understood that by building numerical matrix and to click-through different in matrix Row experiment, can realize determining for suitable dose, it is in doctor or the common skill of clinical scientist of undergoing training using normal experiment In art limit of power.
" CDR " herein is defined by Chothia et al. or Kabat et al..Referring to Chothia C, Lesk AM. (1987) canonical structure (the Canonical structures for the hypervariable of immunoglobulin hypervariable region regions of immunoglobulins).J Mol Biol.,196(4):901-17, is incorporated by as ginseng herein Examine.Referring to Kabat E.A, Wu T.T., Perry H.M., Gottesman K.S. and Foeller C. (1991) immunologys are ground Protein sequence (Sequences of Proteins of Immunological Interest) the .5th edit., NIH studied carefully Publication no.91-3242, US Dept.of Health and Human Services, Washington, DC are herein It is incorporated by as reference.
" cross competition " refers to that antibody or other binding reagents disturb other antibody or knot in Standard Competition combination mensuration Close the ability that reagent is combined with CD19.Antibody or other binding reagents can interfere with another antibody or binding molecule and combined with CD19 Ability or degree, and correspondingly whether can according to the present invention be known as cross competition, Standard Competition combination mensuration can be used To determine.A kind of suitable measure is related to using Biacore technologies (for example, by using 3000 instruments of BIAcore (Biacore, Uppsala, Sweden)), it can use the degree of Applications of surface plasmon resonance measurement interaction.Separately A kind of measure for measuring cross competition uses the method based on ELISA.Described in International Patent Application No. WO 2003/48731 The high throughput method of " epitope combination " antibody based on its cross competition.
Term " epitope " includes any egg that can be combined with antibody specificity or otherwise interact with molecule White determinant (determinant).Epitopic determinants are usually by the chemically active surface group such as amino acid or carbon water of molecule Compounds or carbohydrate side chain composition, it can have specific Three Dimensions Structure, and specific charge characteristic.Epitope can be with It is " linear " or " conformation ".Term " linear epitope " refers to the institute between protein and interacting molecule (such as antibody) The epitope that the primary amino acid sequences (continuous) for having interaction point along protein linearly occur.Term " comformational epitope " refers to The epitope that wherein discontinuous amino acid gathers together in three-dimensional conformation.In comformational epitope, interaction point is across egg The amino acid residue being spaced apart in white matter occurs.
" with reference to same epitope " refers to the ability that antibody or other binding reagents are combined with CD19, and it resists with illustrated Body has same epitope.Illustrated antibody and other antibody can use standard scale bitmap spectral technology true for the epitope of CD19 It is fixed.Epitope maps technology is it is known in the art that it includes the epitope maps scheme in documents below：Methods in Molecular Biology,Vol.66(Glenn E.Morris,Ed.,1996)Humana Press,Totowa,New Jersey.For example, linear epitope can determine by the following method：It is for example, simultaneously synthesizing substantial amounts of on solid support Peptide --- a part of corresponding peptide with protein molecular, and make peptide anti-with antibody while peptide is remained attached on supporter Should.These technologies are known in the art, and are described in documents below：For example, U.S. patents the 4th, 708,871； Geysen et al., (1984) Proc.Natl.Acad.Sci.USA 8:3998-4002；Geysen et al., (1985) Proc.Natl.Acad.Sci.USA 82:78-182；Geysen et al., (1986) Mol.Immunol.23:709-715.It is similar Ground, comformational epitope are easy to identify by determining the space conformation of amino acid, for example, being exchanged by such as hydrogen/deuterium, x- rays crystalline substance Body and two dimensional NMR.See, e.g., epitope maps scheme, it is same as above.The antigenic region of albumen can also use standard antigen Property and hydropathic profile identify, for example, using Omiga 1.0 editions software programs as being obtained from Oxford Molecular Group Come those calculated.The computer program uses Hopp/Woods methods (Hopp et al., (1981) Proc.Natl.Acad.Sci USA 78:3824-3828) determined for antigenic collection of illustrative plates, and use Kyte-Doolittle technologies (Kyte et al., (1982)J.MoI.Biol.157:105-132) it is used for hydropathic profile.
Embodiment
One side in the present disclosure is to be used to treat non Hodgkin lymphom, chronic lymphocytic leukemia And/or the CD19 specific antibodies of acute lymphoblastic leukemia and the combination of phosphoinositide 3-kinase inhibitor.In reality Apply in mode, which is concertedness.
Herein, the combination of exemplary anti-CD19 antibody and Idelalisib in the relevant external models of CLL with playing association Same-action.Since CLL is a kind of B cell relevant disease, and CD19 altimeters in B cell reach, so exemplary combination should When with identical mechanism of action, also synergistic effect should be played in the treatment of other B cell associated conditions such as NHL and ALL. Therefore, the combination of exemplary CD19 specific antibodies and Idelalisib should be in people non Hodgkin lymphom, chronic leaching In the treatment of bar cell leukemia and/or acute lymphoblastic leukemia effectively.Clinical test will confirm exemplary Expection effect of the combination of CD19 specific antibodies and Idelalisib.
Chronic B- cell leukemic cell lines MEC-1 cells (DSMZ#ACC497) are tested.
Assess other cell line：Ramos cells (ATCC CRL-1596) --- a kind of people Burkitt's lymthomas are thin Born of the same parents.HG-3 (DSMZ#ACC765) and Cll (DSMZ#ACC773) is chronic lymphocytic leukemia cells system.Su-DHL 6 (DSMZ#ACC572) and U2932 (DSMZ#ACC633) is diffusivity large B cell lymphoid tumor (DLBCL) cell line.JVM-2(CRL-3002) it is lymphoma mantle cell cell line.BALL-1 (DSMZ#ACC742) is a kind of acute thin into lymph Born of the same parents' property Leukemia Cell Lines.
In this external model MEC-1 cells instruction combination by how people chronic lymphocytic leukemia (CLL) work in treatment.Ramos cells in this external model indicate the combination how people non-Hodgkin's lymph Work in the treatment of knurl (NHL).HG-3 and Cll cells in this external model indicate the combination by how in the chronic of people Work in the treatment of lymphocytic leukemia (CLL).Su-DHL 6 and the instruction of U2932 cells in this external model should How combination will work in the treatment of the non-Hodgkin lymphoma of people.JVM-2 cells instruction in this external model should How combination will work in the treatment of the non-Hodgkin lymphoma of people.BALL-1 cells instruction in this external model should How combination will work in the treatment of the acute lymphoblastic leukemia of people.
The numerical value of Chou indexes and Clark et al. compared with single MOR00208 and Idelalisib, The combination of MOR00208 and Idelalisib significantly acts synergistically in the specific killing of MEC-1 cells.
In short, exemplary anti-CD19 antibody is cooperateing with work with the combination of Idelalisib with being risen in the relevant models of CLL With.Therefore, the combination of exemplary CD19 specific antibodies and Idelalisib should be in people non-Hodgkin lymphoma, chronic leaching In the treatment of bar cell leukemia and/or acute lymphoblastic leukemia effectively.
Since Idelalisib is similar with the mechanism of action of other phosphoinositide 3-kinase inhibitors, because they are all logical Cross and suppress as a kind of PI3K/AKT/mTOR paths (weight that control, metabolism and translation initiation are such as grown for many cell functions Want signal transduction pathway) a part one or more phosphoinositide 3-kinases and work, it is believed that when with exemplary anti- The combination of CD19 antibody and phosphoinositide 3-kinase inhibitor in addition to Idelalisib is treated with non-Hodgkin's lymph During the people of knurl, chronic lymphocytic leukemia and/or acute lymphoblastic leukemia, it should also be recognized that synergistic effect.
Since exemplary anti-CD19 antibody and other anti-CD19 antibody combine CD19, it is believed that with any anti- The treatment of CD19 antibody and phosphoinositide 3-kinase is with non-Hodgkin lymphoma, chronic lymphocytic leukemia and/or acute During the people of lymphoblastic leukemia, also it should be observed that concertedness, wherein anti-CD19 antibody is, such as is described in US patents Patent application serial numbers 12/377,251 (Xencor), WO2005012493, WO2010053716 (Immunomedics)； WO2007002223(Medarex)；WO2008022152(Xencor)；WO2008031056(Medimmune)；WO 2007/ 076950(Merck Patent GmbH)；WO 2009/052431(Seattle Genetics)；And WO2010095031 Those of (Glenmark Pharmaceuticals), it is integrally incorporated by quoting.
In embodiments, the specific antibody of CD19 includes the antibody with following antibody cross competition, the antibody bag (the SEQ ID NO of SYVMH containing sequence:1) HCDR1 areas, sequence NPYNDG (SEQ ID NO:2) HCDR2 areas, sequence GTYYYGTRVFDY(SEQ ID NO:3) HCDR3 areas, sequence RSSKSLQNVNGNTYLY (SEQ ID NO:4) LCDR1 Area, sequence RMSNLNS (SEQ ID NO:5) LCDR2 areas and sequence MQHLEYPIT (SEQ ID NO:6) LCDR3 areas.
In embodiments, the specific antibody of CD19 includes the antibody with following antibody binding same epitope, described anti- Body includes sequence SYVMH (SEQ ID NO:1) HCDR1 areas, sequence NPYNDG (SEQ ID NO:2) HCDR2 areas, sequence GTYYYGTRVFDY(SEQ ID NO:3) HCDR3 areas, sequence RSSKSLQNVNGNTYLY (SEQ ID NO:4) LCDR1 Area, sequence RMSNLNS (SEQ ID NO:5) LCDR2 areas and sequence MQHLEYPIT (SEQ ID NO:6) LCDR3 areas.
In embodiments, the specific antibody of CD19 includes sequence SYVMH (SEQ ID NO:1) HCDR1 areas, sequence NPYNDG(SEQ ID NO:2) HCDR2 areas, sequence GTYYYGTRVFDY (SEQ ID NO:3) HCDR3 areas, sequence RSSKSLQNVNGNTYLY(SEQ ID NO:4) LCDR1 areas, sequence RMSNLNS (SEQ ID NO:5) LCDR2 areas and sequence Arrange MQHLEYPIT (SEQ ID NO:6) LCDR3 areas.
In embodiments, the specific antibody of CD19 includes sequence EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYINPYNDGTKYNEKFQGRVTISSDKSIS TAYMELSSLRSEDTAMYYCARGTYYYGTRVFDYWGQGTLVTVSS(SEQ ID NO:10) variable heavy chain and sequence DIVMTQSPATLSLSPGERATLSCRSSKSLQNVNGNTYLYWFQQKPGQSPQLLIYRMSNLNSGVPDRFSGSGSGTEFT LTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIK(SEQ ID NO:11) variable light.
In some embodiments, the antibody includes following sequence of heavy chain constant domain：
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG TQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP EVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKALPAPEEKTISKTKGQPREPQV YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSC SVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:12)。
In embodiments, CD19 specific antibodies include following sequence of light chain constant domain：
RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:13)。
In embodiments, phosphoinositide 3-kinase inhibitor is Idelalisib.
In embodiments, respectively using the component of the combination, CD19 specific antibodies and Idelalisib.In a reality Apply in mode, Idelalisib is applied before CD19 specific antibodies are applied.In one embodiment, CD19 spies are being applied Idelalisib is applied after heterogenetic antibody.In one embodiment, it is special using the component of the combination, CD19 simultaneously or together Heterogenetic antibody and Idelalisib.
In embodiments, which is pharmaceutical composition.In embodiments, said composition includes acceptable load Body.In embodiments, which is applied with effective dose.
On the other hand, it is SYVMH (SEQ ID NO comprising sequence:1) HCDR1 areas, sequence are NPYNDG (SEQ ID NO:2) HCDR2 areas, sequence are GTYYYGTRVFDY (SEQ ID NO:3) HCDR3 areas, sequence are RSSKSLQNVNGNTYLY(SEQ ID NO:4) LCDR1 areas, sequence are RMSNLNS (SEQ ID NO:5) LCDR2 areas and Sequence is MQHLEYPIT (SEQ ID NO:6) the CD19 specific antibodies in LCDR3 areas and the synergistic combination of Idelalisib exist Can be with compared to the good at least twice of single Idelalisib, three times, four times or five times in the presence of separated human PBMC Effect mediates the killing of MEC-1 cells by ADCC.
One side in the present disclosure include be used for treat non-Hodgkin lymphoma, chronic lymphocytic leukemia and/ Or the CD19 specific antibodies of acute lymphoblastic leukemia and the synergistic combination of Idelalisib, the CD19 specificity Antibody is SYVMH (SEQ ID NO comprising sequence:1) HCDR1 areas, sequence are NPYNDG (SEQ ID NO:HCDR2 areas 2), Sequence is GTYYYGTRVFDY (SEQ ID NO:3) HCDR3 areas, sequence are RSSKSLQNVNGNTYLY (SEQ ID NO:4) LCDR1 areas, sequence be RMSNLNS (SEQ ID NO:5) LCDR2 areas and sequence is MQHLEYPIT (SEQ ID NO:6) LCDR3 areas.In embodiments, non-Hodgkin lymphoma is selected from follicular lymphoma, small lymphocytic lymphoma, mucous membrane Associated lymphoid tissue, marginal zone, diffusivity large B cell, Burkitt's and jacket cell.
On the other hand it is white to include one kind treatment non-Hodgkin lymphoma, chronic lymphocytic in individuals in need The method of blood disease and/or acute lymphoblastic leukemia, this method include applying CD19 specific antibodies and phosphoinositide 3- kinase inhibitors.In the embodiment of this method, CD19 specific antibodies are SYVMH (SEQ ID NO comprising sequence:1) HCDR1 areas, sequence be NPYNDG (SEQ ID NO:2) HCDR2 areas, sequence are GTYYYGTRVFDY (SEQ ID NO:3) HCDR3 areas, sequence be RSSKSLQNVNGNTYLY (SEQ ID NO:4) LCDR1 areas, sequence are RMSNLNS (SEQ ID NO:5) LCDR2 areas and sequence is MQHLEYPIT (SEQ ID NO:6) LCDR3 areas.In the embodiment of this method, Antibody includes exemplary CD19 specific antibodies.In the embodiment of this method, phosphoinositide 3-kinase inhibitor is Idelalisib。
On the other hand include CD19 specific antibodies has this to need in preparation with phosphoinositide 3-kinase inhibitor for treatment Non-Hodgkin lymphoma, chronic lymphocytic leukemia and/or acute lymphoblastic leukemia in the individual wanted Purposes in medicine, this method include applying the medicine comprising CD19 specific antibodies and phosphoinositide 3-kinase inhibitor. In the embodiment of this method, the CD19 specific antibodies are SYVMH (SEQ ID NO comprising sequence:1) HCDR1 areas, sequence It is classified as NPYNDG (SEQ ID NO:2) HCDR2 areas, sequence are GTYYYGTRVFDY (SEQ ID NO:3) HCDR3 areas, sequence It is classified as RSSKSLQNVNGNTYLY (SEQ ID NO:4) LCDR1 areas, sequence are RMSNLNS (SEQ ID NO:5) LCDR2 Area and sequence are MQHLEYPIT (SEQ ID NO:6) LCDR3 areas.In the embodiment of this method, antibody includes example The CD19 specific antibodies of property.In the embodiment of this method, phosphoinositide 3-kinase inhibitor is Idelalisib.
Embodiment
Embodiment 1：Using single MOR00208 and Idelalisib with and combinations thereof to the cytotoxicities of MEC-1 cells
Material
Cell line：Chronic B- cell leukemic cell lines MEC-1 cells (DSMZ#ACC497)；Lymphoma mantle cell cell Be JVM-2 (CRL-3002)；Ramos cells (ATCC CRL-1596), a kind of people Burkitt ' s lymthomas are thin Born of the same parents；HG-3 (DSMZ#ACC765) and Cll (DSMZ#ACC773) is chronic lymphocytic leukemia cells system；Su-DHL 6 (DSMZ#ACC572) and U2932 (DSMZ#ACC633) is diffusivity large B cell lymphoid tumor (DLBCL) cell line；BALL-1 (DSMZ#ACC742) it is acute lymphoblastic leukemia cell line.
The information of supplier is deferred to using the condition of culture of cell line.
Cell culture medium：Iscove's Modified Dulbecco's culture mediums (IMDM), Invitrogen, catalogue Number：31980-048；RPMI1640, Invitrogen, catalog number (Cat.No.)：31870-074；GlutaMAX, Invitrogen, catalog number (Cat.No.)： 35050-38, batch number 1654740；FCS：Sigma catalog number (Cat.No.)s：F7524, batch number：111M3396.
NKs：RPMI1640, has GlutaMAXTM, Invitrogen, catalog number (Cat.No.)：31870-074,10%FCS； Biocoll：Biochrome AG, catalog number (Cat.No.)：L6115, batch number：0034D；MACS NK cell separating kits：Miltenyi Biotec, catalog number (Cat.No.)：130-092-657, batch number：5150327376；Idelalisib：Selleck Chem, batch number： S2226；FCS：Sigma, catalog number (Cat.No.)：F7524, batch number：111M3396；And there is identical Fc areas with MOR00208 RefmAb33 (anti-RSV).
Method
Tested in MEC-1 cell lines single MOR00208 and Idelalisib with and combinations thereof cytotoxicity.
Idelalisib is phosphoinositide 3-kinase inhibitor；More specifically, it blocks phosphoinositide 3-kinase this The δ hypotypes of enzyme, P110 δ.Single Idelalisib is to MEC-1 cells almost without cytotoxic effect.MOR00208 is targeted CD19 simultaneously mediates target cell to kill by ADCC.
It is used as control below：A) MEC-1 cells+RefmAb33+DMSO+NK cells, b) MEC-1 cells+DMSO+NK is thin Born of the same parents, c) MEC-1 cells+DMSO.
Killed using following parameter to measure target cell：Concentration is 0.3,1,3 and 10 μM of Idelalisib；Concentration is 1.5th, the MOR00208 of 0.015 and 0.0015 μ g/ml, and the combination of the MOR00208 and Idelalisib under same concentrations.
In single Idelalisib groups, single MOR00208 groups and MOR00208+Idelalisib combination groups, Before ADCC experiment measure, target cell is pre-processed 7 days with Idelalisib.Target cell is counted and uses 10 μM of CFSE dense eventually Degree is dyed.For the target cell of DMSO processing, 2 are selected：1 effector：Target (E:T) ratio, corresponding to 5x105/ ml's Cell density.E in the cell handled by adjusting inhibitor:T ratios, target cell will increase caused by Idelalisib processing Effect is grown to be included.To NK cell counts and adjusted to 1x106/ml.Target cell kills experiment and is carried out as follows：Use 96 Orifice plate, 100 μ l target cell suspension liquid are added per hole, the cell suspending liquid of the NK cells of 100 μ l is then added into each hole, is obtained 2:1 E:T ratios.By antibody in the medium with (correspond to 1.5-0.0000015 μ g/ml) in the range of 10-0.00001nM into Row dilution.Cell is centrifuged and by target：Effector cell's particle is resuspended in the culture medium or compare accordingly molten that 100 μ l contain antibody In liquid.CO of the experiment at 37 DEG C2When incubation 4 is small in-incubator.It is incubated on ice after ten minutes, 50 μ l is added into each hole DAPI solution (1 μ g/ml of final concentration) is simultaneously incubated 10 minutes on ice.Cell is killed measure and is carried out using FACS-Verse.It is dead Target cell is the DAPI positives.
Data
Six experiments are carried out altogether, to measure by the thin to MEC-1 of the combination mediation of MOR00208 and Idelalisib The ADCC of born of the same parents.In six experiments twice in, data are excluded from analysis because compared with the only control of MEC-1 cells, RefmAb is compareed and the killing of single DMSO control 25% highers of display.The autoreactivity of NK cells hampers the two realities Correct Analysis in testing.
The ADCC dose response curves of experiment 1-4 are shown in Fig. 3-6.
The percentage (%) (initial data) for testing the dead cell of 1-4 is shown in table 1 below -16.
Experiment 1
Table 1：10 μM of Idelalisib
Table 2 3 μM of Idelalisib
Table 3 1 μM of Idelalisib
Table 4 0.3 μM of Idelalisib
Experiment 2
Table 5 10 μM of Idelalisib
Table 6 3 μM of Idelalisib
Table 7 1 μM of Idelalisib
Table 8 0.3 μM of Idelalisib
Experiment 3
Table 9 10 μM of Idelalisib
Table 10 3 μM of Idelalisib
The Idelalisib that 11 1 μM of table
The Idelalisib that 12 0.3 μM of table
Experiment 4
The Idelalisib that 13 10 μM of table
The Idelalisib that 14 3 μM of table
The Idelalisib that 15 1 μM of table
The Idelalisib that 16 0.3 μM of table
The calculating of synergistic effect：Clarke et al.
When a kind of medicine has low activity, such as single Idelalisib has low cell toxicant to MEC-1 cells herein Property activity, can determine to act synergistically with the individually dramatically different statistics evidence of suppression medicine by combining.Referring to Clarke et al., Issues in experimental design and endpoint analysis in the study of experimental cytotoxic agents in vivo in breast cancer and other models, Breast Cancer Research and Treatment 46:255-278 (1997), it is integrally incorporated by quoting.
The dead cell % (initial data) of analytical table 1-16 in the following manner：
Antagonism (AB)/C<(A/C)×(B/C)
It is superimposed (AB)/C=(A/C) × (B/C)
Cooperate with (AB)/C>(A/C)×(B/C)
Wherein A is single use the processing of MOR00208；B is single use the processing of Idelalisib；C is to control The response of DMSO+RefMab33；AB is the combination of A and B processing.
Experiment 1
Table 17:The Clarke analyses of data shown in table 1
The Clarke analyses of data shown in 18 table 2 of table
The Clarke analyses of data shown in 19 table 3 of table
The Clarke analyses of data shown in 20 table 4 of table
Experiment 2
The Clarke analyses of data shown in 21 table 5 of table
The Clarke analyses of data shown in 22 table 6 of table
The Clarke analyses of data shown in 23 table 7 of table
The Clarke analyses of data shown in 24 table 8 of table
Experiment 3
The Clarke analyses of data shown in 25 table 9 of table
The Clarke analyses of data shown in 26 table 10 of table
The Clarke analyses of data shown in 27 table 11 of table
The Clarke analyses of data shown in 28 table 12 of table
Experiment 4
The Clarke analyses of data shown in 29 table 13 of table
The Clarke analyses of data shown in 30 table 14 of table
The Clarke analyses of data shown in 31 table 15 of table
The Clarke analyses of data shown in 32 table 16 of table
As a result
Using the method for Clarke et al., experiment 2-4 at various concentrations shows that MOR00208+Idelalisib is combined Obvious synergistic effect.However, experiment 1 does not show synergistic effect under some concentration, because Idelalisib groups (are shown in Table 1-3) show weaker effect, this effect slightly above control is (than compareing high about 4%).This is compared with a control small (~4%) difference can be attributed to experimental setup in the range of other controls.
Synergistic effect calculates：Combinatorial index (CI)
In order to confirm that Clarke used above et al. is calculated synergistic effect as a result, by combinatorial index (CI) method application In the dead cell % (initial data) of table 1-16.Calculated for CI, we use 0.3,1,3 and 10 μM of Idelalisib and three A MOR208 concentration (1.5,0.015 and 0.0015 μ g/ml).
By quoting the Ting-Chao Chou, the Theoretical Basis, Experimental that are integrally incorporated Design,and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies,Pharmacol Rev 58:621-681 (2006) and by quoting the Chou being integrally incorporated TC,Talalay P,Quantitative analysis of dose-effect relationships:the combined effects of multiple drugs or enzyme inhibitors.Adv Enzyme Regul 22:27-55 (1984) such calculating is described in.The method of Chou-Talalay uses the equivalent line method (CI-isobol of CI- Method) carry out.
Intermediate value effect equation
The effect of inhibitor (such as medicine) is modeled as F by intermediate value effect equationa/Fu=(D/D50) ^m, wherein D are dosage, FaAnd FuBe by with the system fraction (Fa+Fu=1) that is influenced from dosage D；D50 be produce intermediate value effect dosage (such as IC50、ED50、LD50).Constant m determines the shape of dose-effect curve.
We carry out nonlinear regression calculating to estimate parameter m and D50 using GraphPad Prism.
The equivalent line methods of CI-
The equivalent line methods of CI- provide the qualitative assessment of synergy between medicine.Combinatorial index (CI) is from single and group The docs-effect data estimation of composite medicine treatment.CI values are less than 1 and represent cooperative effect；CI=1 represents synergistic effect；CI>1 Represent antagonistic effect.CI values are more remote from 1, and drug interaction (collaboration or antagonism) is more obvious.
In form, the combinatorial index (CI) of composition of medicine treatment is defined as
CI=D1/Dx1+D2/DX2
Here D1 and D2 is the medicine 1 of combination and the dosage of medicine 2 respectively；Dx1 and Dx2 be only with medicine 1 and medicine 2 into Dosage when row treatment can be produced with combining same effect.Dosage Dx1 and Dx2 need the docs-effect from single medicine treatment Data estimation.Substantially, intermediate value effect equation is fitted to the data of each medicine.From the intermediate value effect equation of medicine, Wo Menke Dosage (i.e. D) needed for effect (i.e. Fa, Fu) is produced with estimation.Point from superposition line it is more remote, 1 is bigger with the difference of CI, (cooperate with or Antagonism) effect is stronger.
As a result
Fig. 7-10 is shown based on curve caused by the cooperated computing of Chou.Chou exponential quantities show with individually MOR00208 is compared with Idelalisib, and the combination of MOR00208 and Idelalisib is in all experiment 1-4 in MEC-1 cells Specific killing in show obvious synergistic effect.
The combination of MOR00208 and Idelalisib is synergistically worked in MEC-1CLL cell lines.It is therefore contemplated that The combination of MOR00208 and Idelalisib is collaboration in the treatment of people CLL.
In addition, it is additionally considered that the combination of MOR00208 and Idelalisib in mankind's non-Hodgkin lymphoma (NHL), chronic leaching Also synergistically work in the treatment of bar cell leukemia (CLL) and acute lymphoblastic leukemia (ALL).
It is to be understood that although illustrate exemplary embodiment, but specification, specific embodiment and data are with example The mode of card provides, and is not intended to limit the invention.From discussion, disclosure and the data included herein, the present invention In variations and modifications would is that for the technician it will be apparent that be therefore regarded as the present invention a part.
Sequence table
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Gly Lys Tyr Tyr Cys His Arg Gly Asn Leu Thr Met Ser Phe His Leu
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Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg
290 295 300
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305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Glu Glu
325 330 335
Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
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355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
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Gly Lys
450
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Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe
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Claims (15)

  1. A kind of 1. synergistic combination comprising CD19 specific antibodies and phosphoinositide 3-kinase inhibitor, wherein the antibody includes Sequence is SYVMH (SEQ ID NO:1) HCDR1 areas, sequence are NPYNDG (SEQ ID NO:2) HCDR2 areas, sequence are GTYYYGTRVFDY(SEQ ID NO:3) HCDR3 areas, sequence are RSSKSLQNVNGNTYLY (SEQ ID NO:4) LCDR1 Area, sequence are RMSNLNS (SEQ ID NO:5) LCDR2 areas and sequence is MQHLEYPIT (SEQ ID NO:6) LCDR3 Area, the combination are white for treating non-Hodgkin lymphoma, chronic lymphocytic leukemia and/or Acute Lymphoblastic Blood disease.
  2. 2. combination according to claim 2, wherein the antibody includes sequence EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYINPYNDGTKYNEKFQGRVTISSDKSIS TAYMELSSLRSEDTAMYYCARGTYYYGTRVFDYWGQGTLVTVSS(SEQ ID NO:10) variable heavy chain and sequence DIVMTQSPATLSLSPGERATLSCRSSKSLQNVNGNTYLYWFQQKPGQSPQLLIYRMSNLNSGVPDRFSGSGSGTEFT LTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIK(SEQ ID NO:11) variable light.
  3. 3. combination according to any one of the preceding claims, wherein the antibody includes sequence ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG TQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP EVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKALPAPEEKTISKTKGQPREPQV YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSC SVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:12) heavy chain constant domain.
  4. 4. combination according to any one of the preceding claims, wherein the antibody includes sequence RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:13) light chain constant domain.
  5. 5. combination according to any one of the preceding claims, wherein the CD19 specific antibodies and the phosphoinositide 3- kinase inhibitors are applied respectively.
  6. 6. combination according to claim 5, wherein the CD19 specific antibodies and the phosphoinositide 3-kinase suppress Agent is physically applied respectively.
  7. 7. combination according to claim 5, wherein the CD19 specific antibodies and the phosphoinositide 3-kinase suppress Agent is applied respectively in time.
  8. 8. according to the combination any one of claim 1-4, wherein the CD19 specific antibodies and the phosphoinositide 3- kinase inhibitors are applied together.
  9. 9. combination according to any one of the preceding claims, wherein being applied before the CD19 specific antibodies are applied The phosphoinositide 3-kinase inhibitor.
  10. 10. combination according to any one of the preceding claims, wherein being applied after the CD19 specific antibodies are applied With the phosphoinositide 3-kinase inhibitor.
  11. 11. according to the combination any one of claim 1-4, wherein the phosphoinositide 3-kinase inhibitor and described CD19 specific antibodies are administered simultaneously.
  12. 12. combination according to any one of the preceding claims, wherein the phosphoinositide 3-kinase inhibitor is Idelalisib。
  13. 13. combination according to any one of the preceding claims, it is used to treat non-Hodgkin lymphoma, wherein described non- Hodgkin lymphoma is selected from follicular lymphoma, small lymphocytic lymphoma, mucosa-associated lymphoid tissue, marginal zone, more Unrestrained property large B cell, Burkitt's and jacket cell.
  14. 14. combination according to any one of the preceding claims, it is used to treat chronic lymphocytic leukemia.
  15. 15. combination according to any one of the preceding claims, it is used to treat acute lymphoblastic leukemia.
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